Evaluation of a personalised adherence intervention to improve photoprotection in adults with Xeroderma Pigmentosum (XP): protocol for the trial of XPAND

Introduction Poor adherence to photoprotection for people with xeroderma pigmentosum (XP) can be life-threatening. A randomised controlled trial (RCT) is being conducted to test the efficacy of a personalised adherence intervention (XPAND) to reduce the level of ultraviolet radiation (UVR) reaching the face, by improving photoprotection activities in adults with XP. Methods and analysis A two-armed parallel groups RCT, where we randomised 24 patients with suboptimal adherence to either an intervention group who received XPAND in 2018 or a delayed intervention group who will receive XPAND in 2019. XPAND involves seven sessions, one-to-one with a facilitator, using behaviour change techniques and specially designed materials to target barriers to photoprotection. Following baseline assessment in April 2018 (t0) and intervention, the primary outcome will be measured across 21 consecutive days in June and July 2018 (t1). The primary outcome is the average daily UVR dose to the face (D-to-F), calculated by combining objective UVR exposure at the wrist (measured by a dosimeter) with face photoprotection activities recorded on a daily UVR protection diary. Secondary outcomes include average daily UVR D-to-F across 21 days in August (t2); psychosocial process variables measured by daily questions (t0, t1, t2) and self-report questionnaires (t0, t1, t2, December 2018 (t3)). Intervention cost-utility is assessed by service use and personal cost questionnaires (t0, t3). The delayed intervention control arm participants will complete three further assessments in April 2019 (t4) and June–July 2019 (t5), and December 2019 (t6) with dosimetry and UVR protection diary completed for 21 days at t4 and t5. A process evaluation will be conducted using mixed methods. Ethics and dissemination Ethical approval has been received from West London & GTAC REC 17/LO/2110. Results will be disseminated in peer-reviewed journals and at conferences. This study tests a novel intervention, which, if successful, will be integrated into routine care. Trial registration number NCT03445052; Pre-results.


INTRODUCTION
Xeroderma Pigmentosum (XP) is a very rare genetic condition, where the body is unable to repair ultraviolet radiation (UVR)-induced damage to DNA caused by daylight 1 .
Any UVR exposure dramatically increases the chances of developing skin and eye cancers (e.g., rates of non-melanoma skin cancer increase 10,000 fold) 2 . Photoprotection is recommended for the healthy population and those taking medications which may cause photosensitivity. However, it is essential for people with XP. There is currently no cure for this disease and the only way to minimise and delay the cancers is meticulous and absolute photoprotection every day. Photoprotection involves a complex set of behaviours (i.e., application of broad-spectrum SPF50 sunscreen, wearing long sleeves and long trousers or skirts, wide brimmed hat, glasses, face scarf or buff and avoiding UVR exposure by staying indoors). The best way of protecting the face is by wearing a face visor (a legionnaire style hat with a UVR-protective transparent film at the front). Analysis of self-reported photoprotection used by 21 adults with XP in the UK revealed that over half were using 'very poor' or no photoprotection for at least 20% of all outdoor time 3 . This poor photoprotection has life-threatening consequences.
In common with other rare conditions 4 , little is known about the psychological and behavioural patient-related factors that have the potential to improve health outcomes in patients with XP. In recognition of this deficit, the National Institute of Health Research  adherence using complex mixed-methods research (qualitative interviews; cross-sectional survey; n-of-1; diary-dosimeter measures) 5 (known as "Phase One") and to use this knowledge to design and test an intervention to improve adherence ("Phase Two"). We identified 17 modifiable psychosocial drivers of non-adherence to photoprotection activities from Phase One. These drivers or barriers to optimal photoprotection relate to factors influencing the motivation to protect (e.g., doubts about perceived necessity of photoprotection) and volitional factors limiting the enactment of photoprotection activities, even if motivation is high (e.g., lack of habit). Findings from the mixed-methods research studies are published separately 3 6 7 .
Nobody has attempted to systematically develop an adherence intervention to improve photoprotection in XP. However, there is growing support for interventions focused on changing patient beliefs about their illness and treatment, translating into improvements in adherence across a range of chronic conditions [8][9][10] . This suggests that addressing unhelpful illness and treatment beliefs may be an important treatment target for photoprotection in XP. Furthermore, a recent systematic review found evidence in support of the effectiveness of psychosocial interventions to improve adherence to photoprotective activities among non-XP individuals at elevated risk for melanoma (due to personal or family history 11 ).
We designed a personalised intervention titled, 'XPAND: Enhancing XP Photoprotection Activities -New Directions', using Intervention Mapping 12

. Intervention
Mapping starts by breaking the desired behaviour and determinants of behaviour into constituent parts, which are mapped to theory and translated to intervention components.
Relevant theories to guide the intervention design included the Necessity and Concerns  Framework (not a theory itself but it combines the components of social cognition models used to explain behaviour) 15 . A full description of the development of the intervention, the process of personalisation, and the final intervention product will be reported separately.
This paper describes the protocol for a randomised controlled trial (RCT) to test the efficacy of XPAND to lower the dose of UVR reaching the face, by improving adherence to photoprotection. This can be achieved by minimising overall UVR exposure (i.e., time spent outside) and by increasing level of photoprotection worn or applied when outside. The primary objective is to reduce the average daily UVR dose to the face (D-to-F) across 21 days in June to July (2018), immediately after the delivery of the main intervention. Secondary objectives are: to maintain reductions in average daily UVR D-to-F across 21 days in August 2018 (after a booster session has been delivered to the intervention group); to increase and then maintain daily ratings of mood, self-efficacy, goal priority, automaticity and photoprotection activities across the two 21-day periods. Tertiary objectives are to explore intervention-related changes from baseline. A qualitative process evaluation will investigate the acceptability, feasibility, and change mechanisms from the perspective of the participant. We will conduct a cost-utility analysis, which will indicate whether implementation into clinical care is economically viable.

Participants and recruitment
People diagnosed with XP and registered at the National XP Service at Guy's and St Thomas' NHS Foundation Trust will be recruited into the trial. Eligible patients will be sent an invitation letter, followed by a telephone call from the research nurse, and those interested will be sent the study information leaflet. Following a second call, if they wish to participate, they will give written consent at a home visit. Patients will be reminded that participation in the study is voluntary and that they may withdraw at any time. No payment will be given for participation. Screening and recruitment took place between February-March 2018.  3. Diagnosed with current clinical depression or anxiety, as detailed in medical notes, or confirmed after completion of Hospital Anxiety and Depression Scale (HADS) 17 at the baseline home visit

Study design and flowchart
The XPAND trial is a phase-II two-armed parallel group RCT, with a delayed intervention control arm. Participants are randomised to either the intervention group who receive the XPAND intervention in addition to routine care between April and June 2018 or to the control group who receive routine care in 2018 and then XPAND between April and June 2019. The delayed intervention control group is included to maximise information collection about the intervention due to the extremely rare nature of XP. For example, achievable sample sizes limit the ability to test between-group differences for the psychosocial outcomes with acceptable power and the delayed intervention group allows for intervention-related changes from baseline testing, which is less robust but still useful.
Patient flow through the study is described in Figure 1. The baseline assessment takes place in April 2018 (t0). Post-randomisation assessments take place after completion of the intervention in June to July 2018 (t1), after a booster session in August 2018 (t2), and a longterm follow-up in December 2018 (t3). All participants wear a wrist-worn UVR dosimeter continuously from t0-t2 and complete daily UVR protection diaries for 21 consecutive days at each assessment time point. At each assessment, participants additionally complete patient reported outcomes. The t3 follow-up does not involve dosimetry or daily UVR protection diary. In addition, the delayed intervention control arm only complete three further assessments in April 2019 (t4) and June-July 2019 (t5), and December 2019 (t6) with dosimetry and daily UVR protection diary completed for 21 days at t4 and t5.

Randomisation
Participants will be randomised, using an equal allocation ratio, to receive XPAND immediately (2018) or to the delayed group stratified by burning type to attempt to balance those with an extreme versus normal burning response. Participants who are in the same family will be randomised as a cluster to the same group to avoid contamination. Since all participants will be recruited at the point of randomisation, the trial statistician (SN) will generate a random allocation for all participants. The lead researcher (JWa) will randomly assign (coin toss) group 1 and group 2 to be the intervention or control. To protect the integrity of the randomisation, participants in the immediate intervention group will be asked not to reveal their allocation to those outside their immediate family. Group allocation will be concealed from the XP clinical team who are not part of the research team (excluding the PI) to avoid inadvertent changes to the standard care of these participants during the trial (e.g., greater/lesser discussion of adherence during routine clinical appointments). The primary outcome is the average daily UVR D-to-F (standard erythemal dose; SED), across 21 consecutive days between June and July 2018 (t1), following completion of six out of seven intervention sessions by the intervention group. UVR D-to-F is estimated by combining data from a UVR dosimeter worn on the wrist (SunSaver 3, Bispebjerg Hospital, Copenhagen, Denmark) 18 and the patient's photoprotective activities, self-reported using the daily UVR protection diary. The dosimeter was set to measure UVR levels every five seconds and record the average every 5 minutes, which has been validated as providing reliable measurements of total UVR exposure over the course of a day 19 . The combination of the daily UVR protection diary and dosimeter to estimate UVR D-to-F has been used in our earlier research with this population (Phase One) and demonstrated to function sufficiently well to be the primary outcome in this trial. The paper-based daily UVR protection diary allows participants to record periods of time spent outside (in 15-minute intervals) and the timing of any specific photoprotection activities while outside (i.e., wearing a face visor, hat, hoodie worn-up, glasses, scarf or face buff, or applying sunscreen and lip-block). UVR D-to-F will be calculated using the dose recorded at the wrist weighted by the level of protection provided by the combination facial photoprotection behaviours used 5 .

Secondary outcomes
The following outcomes relate to between-group comparisons in 2018 and are recorded on the daily UVR protection diary. UVR-related outcomes also use data from the dosimeter. a. Average daily UVR D-to-F across 21 consecutive days in August 2018 (t2). This is to investigate the stability of any improvement identified in the primary outcome b. Average daily total UVR exposure during each of the 21-day periods (t1, t2) and the average daily time outside across all daylight hours and restricted to 11-3pm, when UVR levels are at their highest. This data will be gathered from the dosimeter and the UVR protection diary.
c. Average daily proportion of time outside across daylight hours and between 11-3pm with "very good" or "excellent" face photoprotection during each of the 21-day periods (t1, t2). The categorisations relate to the Daily Photoprotection Scale (DPS) 3 developed for the Phase One n-of-1 study in consultation with the UK XP clinical team. Facial photoprotection activities (excluding sunscreen) are ranked according to their relative level of photoprotection. The following combinations are classed as "very good photoprotection": hat, glasses and scarf/buff; hat, glasses, scarf/buff and hoodie. "Excellent photoprotection" is wearing a face visor, which completely covers the face.  13 assessment questions used in our n-of-1 study 3 (e.g., How much do you agree that UVR protection of your face today was something you did automatically without thinking 0=strongly disagree -10=strongly agree) and are included on the UVR protection diary.

Tertiary outcomes
The following outcomes are assessed once, at the start of each 21-day period (t0, t1, t2, t3). Health-related quality of life, psychological well-being, automaticity of photoprotection activities, self-efficacy in the context of barriers, and self-rated photoprotection adherence will be assessed using self-report questionnaires. Data will be combined across t1 and t2 to assess proximal impact of the intervention and t3 will be used to assess stability of impact.
See Table 1 for the schedule of self-reported measures.
a. Health-related quality of life will be assessed using the EQ-5D-5L 20 b. Emotional well-being will be measured by the Short-form Warwick Edinburgh Mental Well-Being scale (SWEMWBS) 21 c. Automaticity of photoprotection activities will be assessed using the 4-item Self-Report Behavioural Automaticity Index (SRBAI) 22 , adapted to photoprotection. It is a validated subscale of the Self-Report Habit Index 23 which focuses on the automaticity of behaviour. It asks respondents to rate the extent to which they agree with each statement on a seven-point Likert-type scale [e.g., UVR photoprotection is something I do without thinking (1= strongly disagree-7= strongly agree)]. The average of responses gives a score between 1 and 7, with higher scores indicating greater automaticity. 14 d. Self-efficacy to photoprotect will be measured using a 21-item scale [Photoprotection Self-Efficacy Questionnaire (PhotoSEQ)] developed for this study, as no validated questionnaire specific to photoprotection activities in the presence of barriers, as recommended by Bandura (2006) 24 , was identified. Three items ask the respondent to rate their level of confidence that they can carry out a type of photoprotection activity (e.g., shifting timing and/or duration of outdoor activity, photoprotection using clothing, correctly apply sunscreen) on a ten-point scale (0=Not at all -10=very confident); two items ask separately about confidence to wear photoprotective clothing and apply sunscreen in the presence of nine different barriers in the following 4 weeks [e.g., How confident are you that you can photoprotect even if/when: unexpected things get in the way]. Two subscales are calculated, an average self-efficacy score for sunscreen and similarly for photoprotective clothing and shifting time/duration of activity. Higher scores indicate greater self-efficacy. e. A secondary brief measure of photoprotection activities was developed to assess photoprotection to indicate whether improvements in photoprotection are maintained, when participants will not be completing the daily UVR protection diary at t3. To allow comparison with the diary, it will be completed at all follow-up points. The Brief Photoprotection Adherence Questionnaire (BPAQ) has 5 items and assesses duration of time outdoors, and photoprotection used when outdoors during the previous 7 days.
Three items assess how often respondents wore protective clothing (e.g., When you went outside, how often did you protect your face against UVR using protective clothing? 0=never -10=all the time); the number of days sunscreen was applied in the morning (0-7 days); and how often sunscreen was re-applied when outdoors for longer periods (0=not at all -10=always). Two items ask respondents to estimate average duration of time outdoors each day (Never, <30mins, 31mins-1 hour, 2 hours, upwards in hourly intervals to >8 hours) and average duration of time outdoors each day between 11am-3pm when environmental UVR levels are highest. Each item will be analysed separately.
Further exploratory analyses will examine change from baseline incorporating the delayed intervention group allowing for higher power to assess intervention-related changes. These will be undertaken unblinded to group allocation after main efficacy analyses are complete. All assessment materials developed for this study are included in supplementary files.

The XPAND intervention
XPAND is composed of a combination of one-to-one sessions and materials purposedesigned to target barriers to photoprotection. It was designed to be delivered by a healthcare professional (HCP) without specialist psychological training (e.g., clinical nurse specialist). In the trial context, facilitators will be two psychologists and a research nurse.

One-to-one sessions
Facilitators will deliver 7x one-to-one sessions to each participant. Further information on the structure of the intervention is available in Figure 2. Each session will include a combination of personalised and generic content. The intervention content and techniques were systematically developed and selected using Intervention Mapping 12 . Core strategies delivered to all participants will include those to increase self-efficacy, self-regulatory skills, and the automaticity of photoprotection. In addition, personalised modules will be delivered, as needed, selected initially based on data collected in Phase One studies and a profiling questionnaire, and iteratively as additional barriers emerge during the sessions.
The facilitators will use a communication style consistent with Motivational Interviewing 25 .
They will be guided by a manual, including theory-based behaviour change techniques (BCTs) mapped to a recognised taxonomy 26 and specific techniques from other therapeutic approaches (e.g., Acceptance and Commitment Therapy) 27 .

Intervention materials
Patient-facing materials have been developed and will be provided to participants in session 1 and used throughout the intervention to facilitate discussion, provide real-life examples, and reinforce the concepts and skills discussed during the sessions. These are summarised in Figure 2.
[Please insert Figure 2 here]

Sample size calculations
The target sample size for the study is a total of 24 patients (i.e. 12 per group), which was based on the ability to detect an average daily UVR D-to-F difference of 0.10 SED between the groups during the June to July 2018 assessment period. This difference was considered clinically meaningful and potentially achievable due to the personalised nature of the intervention. From our Phase One study of UVR exposure, the average daily UVR D- The main efficacy analyses will be conducted by the trial statistician (SN) following a prespecified analysis plan and blind to group allocation. The analysis will follow the intention to treat principle with individuals analysed within the groups to which they were randomised irrespective of whether they received or persisted with the intervention.
The treatment effect on the primary outcome of daily UVR D-to-F over 21 days between June and July 2018 and secondary outcome of daily UVR D-to-F over 21 days in August will be estimated simultaneously using a linear mixed model. Given the skewed distribution of UVR D-to-F, a logarithmic transformation will be applied and robust standard errors will be estimated. A random intercept will account for the repeated assessments of UVR D-to-F within individuals across all 42 days, with an autoregressive error structure to account for correlation between assessments across successive days. In addition to the dummy coded group variable, other covariates in the model include a dummy coded variable for the assessment period (June-July vs August), an assessment period by group interaction, the patients baseline average daily UVR, an indictor variable for the patients propensity to burn, and the background level of UVR recorded by the observatory closest to the patients' house on the day. Data will be summarised as the empirical Bayes estimate of the average daily UVR D-to-F in SEDs for each assessment period for each group.
Treatment effects for average daily levels of mood, self-efficacy, goal priority, automaticity and time outside will be analysed for both assessment periods simultaneously using mixed-effects as described above. Treatment effects for adherence, self-efficacy, automaticity, QoL, and psychological well-being taken at the start of the June and August assessment periods will also be estimated using linear mixed models but will specify an unconstrained error structure. It is not anticipated that transformation will be required to account for skew in any of these outcomes; however, robust standard errors will be estimated. Covariates included in the analysis will be the same as above except that baseline levels of the outcomes will be included in place of baseline average daily UVR D-to-F.
Further exploratory analysis using dynamic regression models will evaluate changes in both level and variability in daily UVR exposure over time between March and September, accounting for treatment using a regression discontinuity approach. This is possible as the dosimeter will be worn for the entire period. However, due to patient burden and since the UVR protection diary is only completed for three-week intervals, it will also be necessary to calculate UVR D-to-F using average daily photoprotection during the pre and post diary intervals. This differs from the main analysis where UVR D-to-F is calculated directly based on photoprotection activities recorded on the diary.

Process evaluation
A mixed-methods process evaluation, using qualitative interviews and self-report measures, will explore the acceptability of the intervention, changes in photoprotection activities, and psychosocial mechanisms of change. A brief intervention feedback questionnaire, completed immediately after session 6, will be used to record more proximal perceptions of the main content of intervention. Responses to this questionnaire and the profiling questionnaire (see Figure 2) will be used to guide prompts during these interviews and give insight into psychosocial mechanisms of change.
The feedback questionnaire is adapted from one used to assess a fat reduction intervention 28 . It has 5-items assessing overall perceptions of the programme and its components, the impact on photoprotection activities, and whether psychosocial variables have changed as a result of the intervention. The questions assess the extent to which respondents agree with statements about the intervention (e.g., "Overall the programme was interesting" 1=strongly disagree -5=completely agree).
In-depth qualitative interviews will be conducted by a research nurse and health psychologist who were involved in the design and delivery of the intervention. They will not interview participants to whom they delivered the intervention. Interviews will be based on a topic guide and will explore participants' views of and experiences with XPAND, including more practical delivery-related aspects, such as the optimal number of sessions, preference for telephone or skype sessions, and the value of any further booster sessions. All interviews will be audio-recorded, transcribed, and coded using thematic analysis 29 30 in NVivo10.

Fidelity Assurance
A fidelity assessment will be undertaken to examine the extent to which facilitators delivered the key components of the intervention, specified in the intervention manual, during the face-to-face sessions. An independent researcher will apply a fidelity checklist to transcripts of all the session 1s and a random selection of subsequent sessions.

Evaluation of the cost-utility of XPAND
A decision model will be used to assess the cost-effectiveness of the intervention.
Decision models allow outcomes and costs associated with alternative care process to be investigated via simulations. Model structures simplify the care process such that specific aspects can be focussed on. Advantages of these models are that they can be adapted to reflect the outcomes and costs that occur in a variety of settings (and therefore aid generalisability); they allow evidence to be generated in a time and cost-efficient way; and they enable interventions to be evaluated that may be precluded using trial methods. The structure of the model to be used here will be developed by the health economists in collaboration with the clinical researchers, and will consist of health states that patients may be in over time. Transition between the states will be informed by literature on the progression of the condition, expert opinion, and data collected through the trial. The impact of the intervention on these transitions will be determined through the clinical trial.
A health service perspective will be used followed by a societal perspective, which will incorporate broader costs.
Service use will be measured via completion of a Client Service Receipt Inventory (CSRI) 31 . This retrospectively assesses use of primary and secondary healthcare services (including surgical interventions), social care, tests/investigations, and aids and adaptations (see supplementary files for Service Use Questionnaire). The cost of these inputs will be calculated by combining the service use data with appropriate unit cost information. Other impacts of XP include additional financial costs for the patient (e.g., sunscreen); and time lost from work/education by patients (e.g., to attend appointments, receive treatment, manage symptoms). Costs of these effects will be calculated using average wage rates and information on returns to education. Costs will be combined with quality-adjusted life years (QALYs) derived from the EQ-5D-5L. The estimated cost of the intervention will be based on staff time required to deliver it, plus additional training and materials.

Trial management
An independent Trial Steering Committee (TSC) attended by the research team, two independent researchers, and one PPI panel member will meet every 3 months to provide and reported to the TSC, who will make a judgement on the link to the trial and recommend modifications or discontinuing trial as appropriate.

Patient and Public Involvement
Patient and Public Involvement (PPI) has been integral to every step in the development of this protocol. The PPI panel advised on the study design, particularly related to participant burden of completion of the daily UVR protection diary, which informed the decision to limit the follow-up of the delayed intervention control group to a single period of 21 days (June-July 2019, t5). In addition, the panel reviewed all the XPAND intervention participant-facing materials which helped ensure they were appropriate and acceptable.
The PPI panel were not involved in the recruitment process. A summary of research findings will be sent to all participants and published papers will be made available.

ETHICS AND DISSEMINATION
� You only need to record the time you spend outside if it was for 10 minutes or longer � "OUTSIDE" is any amount of time longer than 10 minutes you did not spend in a building "OUTSIDE" includes time spent travelling in cars, buses or trains � Our grid is split into 15 minute blocks, start your line at the nearest block � If you can't remember exactly or you are unsure give us your best guess! � Try to fill out the diary at the end of each day. It will be easier to do when it is fresh in your mind. If you do forget, don't worry! Fill it out as soon as you remember. Thank you very much for taking the time to complete the daily diary.
Daily diary example overleaf Your daily diary UVR We are interested in your views about your UVR protection each day and your general mood. There are four short questions to complete. Don't take too long thinking about your responses. Your immediate reaction to each question will probably be more accurate than a long thought out response. Please circle the number that best corresponds to your views on that day.  Let us know if you wore any of these things today by marking a line on the diary  We know people adjust ultraviolet radiation (UVR) protection to fit in with their everyday life. We are interested in how you protected against UVR in the last week.
Please circle the number that best corresponds to your views: Thinking about your UVR protection over the last week

No Yes
Help in the house (for example cooking or cleaning)

No Yes
Help outside the house (for example shopping or transport)

No Yes
Going with you to medical appointment  We are interested in your own personal views about XP and ultraviolet (UVR) protection. There are no right or wrong answers.

Approximately how much would you estimate that you / your household has paid in the last 6 months for these items? If you paid for items that were a one-off cost longer than 6 months ago, please record these in the "one-off cost" column (take a best and approximate guess, and do not spend too long on this -we realise it is not possible to be completely accurate for this!) :
Answering these questions will help us tailor the XP and programme to your needs.
When we say UVR protection we mean anything you do to protect your face from UVR (e.g. sunscreen, clothing, staying indoors).
It will take about 5 minutes to complete.
Please circle the number that best corresponds to your views:

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions 10 Allocation concealmen t mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 10 Implementat ion 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions 10 Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how 10, 16 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial Can be obtained from authors

Data collection methods 18a
Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol Definition of analysis population relating to protocol nonadherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation)

9-15
Can be obtained from authors

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial n/a

Harms 22
Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct

20-21
Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor Can be obtained from authors

Strengths and limitations of this study
 To the best of our knowledge, this is the first RCT to evaluate an adherence intervention designed to improve photoprotection in people diagnosed with XP.
 We have a primary outcome which is clinically relevant.
 We control for seasonal differences in environmental UVR exposure by comparing between groups across the same weeks.
 We include a process evaluation to understand participant views of XPAND which will be important when integrating the intervention into current clinical care.
 Recruitment and retention of participants may be difficult in this extremely rare disease. Developing a psychological intervention to improve ultraviolet protection and clinical outcomes in XP). The aims of the grant were two-fold: to identify the drivers of non- adherence using complex mixed-methods research (qualitative interviews; cross-sectional survey; n-of-1; diary-dosimeter measures) 5 (known as "Phase One") and to use this knowledge to design and test an intervention to improve adherence ("Phase Two"). We identified 17 modifiable psychosocial drivers of non-adherence to photoprotection activities from Phase One. These drivers or barriers to optimal photoprotection relate to factors influencing the motivation to protect (e.g., doubts about perceived necessity of photoprotection) and volitional factors limiting the enactment of photoprotection activities, even if motivation is high (e.g., lack of habit). Findings from the mixed-methods research studies are published separately 3 6 7 .
We aimed to systematically develop an adherence intervention to improve photoprotection in XP. There is growing support for interventions focused on changing patient beliefs about their illness and treatment, translating into improvements in adherence across a range of chronic conditions [8][9][10] . This suggests that addressing unhelpful illness and treatment beliefs may be an important treatment target for photoprotection in XP. Furthermore, a recent systematic review found evidence in support of the effectiveness of psychosocial interventions to improve adherence to photoprotective activities among non-XP individuals at elevated risk for melanoma (due to personal or family history 11 ).
We designed a personalised intervention titled, 'XPAND: Enhancing XP used to explain behaviour) 15 . A full description of the development of the intervention, the process of personalisation, and the final intervention product will be reported separately.
This paper describes the protocol for a randomised controlled trial (RCT) to test the efficacy of XPAND to lower the dose of UVR reaching the face, by improving adherence to photoprotection. This can be achieved by minimising overall UVR exposure (i.e., time spent outside) and by increasing level of photoprotection worn or applied when outside. The primary objective is to reduce the average daily UVR dose to the face (D-to-F) across 21 days in June to July (2018), immediately after the delivery of the main intervention. Secondary objectives are: to maintain reductions in average daily UVR D-to-F across 21 days in August 2018 (after a booster session has been delivered to the intervention group); to increase and then maintain daily ratings of mood, self-efficacy, goal priority, automaticity and photoprotection activities across the two 21-day periods. Tertiary objectives are to explore intervention-related changes from baseline. A qualitative process evaluation will investigate the acceptability, feasibility, and change mechanisms from the perspective of the participant. We will conduct a cost-utility analysis, which will indicate whether implementation into clinical care is economically viable.

Participants and recruitment
People diagnosed with XP and registered at the National XP Service at Guy's and St Thomas' NHS Foundation Trust will be recruited into the trial. Eligible patients will be sent an invitation letter, followed by a telephone call from the research nurse, and those interested will be sent the study information leaflet. Following a second call, if they wish to participate, they will give written consent at a home visit. Patients will be reminded that

Study design and flowchart
The XPAND trial is a phase-II two-armed parallel group RCT, with a delayed intervention control arm. Participants are randomised to either the intervention group who receive the XPAND intervention in addition to routine care between April and June 2018 or to the control group who receive routine care in 2018 and then XPAND between April and June 2019. The delayed intervention control group is included to maximise information collection about the intervention due to the extremely rare nature of XP. For example, achievable sample sizes limit the ability to test between-group differences for the psychosocial outcomes with acceptable power and the delayed intervention group allows for intervention-related changes from baseline testing, which is less robust but still useful.
Patient flow through the study is described in Figure 1.  further assessments in April 2019 (t4) and June-July 2019 (t5), and December 2019 (t6) with dosimetry and daily UVR protection diary completed for 21 days at t4 and t5.
A nested qualitative study examining fidelity, acceptability, and mechanisms of change will be conducted in the intervention group after the August assessment period is completed.
[please insert Figure 1 here] The study is funded by the NIHR Programme Grants for Applied Research scheme (RP-

Randomisation
Participants will be randomised, in blocks using an equal allocation ratio, to receive XPAND immediately (2018) or to the delayed group stratified by burning type to attempt to balance those with an extreme (i.e., scoring between 1-3 on the sunburn severity score 18 ) versus normal burning response. Participants who are in the same family will be randomised as a cluster to the same group to avoid contamination. Since all participants will be recruited at the point of randomisation, the trial statistician (SN) will generate a random allocation for all participants together as using fixed block sizes to ensure equal allocation to both groups.
The lead researcher (JWa) will randomly assign (coin toss) group 1 and group 2 to be the intervention or control, to which the statistician will be masked. To protect the integrity of the randomisation, participants in the immediate intervention group will be asked not to reveal their allocation to those outside their immediate family. Group allocation will be concealed from the XP clinical team who are not part of the research team (excluding the PI) to avoid inadvertent changes to the standard care of these participants during the trial (e.g., greater/lesser discussion of adherence during routine clinical appointments).

Primary outcome
The primary outcome is the average daily UVR D-to-F (standard erythemal dose; SED), across 21 consecutive days between June and July 2018 (t1), following completion of six out of seven intervention sessions by the intervention group. UVR D-to-F is estimated by combining data from a UVR dosimeter worn on the wrist (SunSaver 3, Bispebjerg Hospital, Copenhagen, Denmark) 19 and the patient's photoprotective activities, self-reported using the daily UVR protection diary. The dosimeter was set to measure UVR levels every five seconds and record the average every 5 minutes, which has been validated as providing reliable measurements of total UVR exposure over the course of a day 20 . The combination of the daily UVR protection diary and dosimeter to estimate UVR D-to-F has been used in our earlier research with this population (Phase One) and demonstrated to function sufficiently well to be the primary outcome in this trial. The paper-based daily UVR protection diary allows participants to record periods of time spent outside (in 15-minute intervals) and the timing of any specific photoprotection activities while outside (i.e., wearing a face visor, hat, hoodie worn-up, glasses, scarf or face buff, or applying sunscreen and lip-block). UVR D-to-F will be calculated using the dose recorded at the wrist weighted by the level of protection provided by the combination facial photoprotection behaviours used 5 .

Secondary outcomes
The following outcomes relate to between-group comparisons in 2018 and are recorded on the daily UVR protection diary. UVR-related outcomes also use data from the dosimeter. efficacy to manage barriers during the two follow-up periods (t1, t2) will be assessed. The single items have been adapted from ecological momentary assessment questions used in our n-of-1 study 3 (e.g., How much do you agree that UVR protection of your face today was something you did automatically without thinking 0=strongly disagree -10=strongly agree) and are included on the UVR protection diary.

Tertiary outcomes
The following outcomes are assessed once, at the start of each 21-day period (t0, t1, t2, t3). Health-related quality of life (HRQoL), psychological well-being, automaticity of photoprotection activities, self-efficacy in the context of barriers, and self-rated photoprotection adherence will be measured using self-report questionnaires. Data will be combined across t1 and t2 to assess proximal impact of the intervention and t3 will be used to assess stability of impact.
See Table 1 for the schedule of self-reported measures.
a. HRQoL will be assessed using the EQ-5D-5L 21 b. Emotional well-being will be measured by the Short-form Warwick Edinburgh Mental Well-Being scale (SWEMWBS) 22 c. Automaticity of photoprotection activities will be assessed using the 4-item Self-Report Behavioural Automaticity Index (SRBAI) 23 , adapted to photoprotection. It is a validated subscale of the Self-Report Habit Index 24 which focuses on the automaticity of behaviour. It asks respondents to rate the extent to which they agree with each statement on a seven-point Likert-type scale [e.g., UVR photoprotection is something I sunscreen was applied in the morning (0-7 days); and how often sunscreen was reapplied when outdoors for longer periods (0=not at all -10=always). Two items ask respondents to estimate average duration of time outdoors each day (Never, <30mins, 31mins-1 hour, 2 hours, upwards in hourly intervals to >8 hours) and average duration of time outdoors each day between 11am-3pm when environmental UVR levels are highest. Each item will be analysed separately.
Further exploratory analyses will examine change from baseline incorporating the delayed intervention group allowing for higher power to assess intervention-related changes. These will be undertaken unblinded to group allocation after main efficacy analyses are complete. All assessment materials developed for this study are included in supplementary files.

The XPAND intervention
XPAND is composed of a combination of one-to-one sessions and materials purposedesigned to target barriers to photoprotection. It was designed to be delivered by a healthcare professional (HCP) without specialist psychological training (e.g., clinical nurse specialist). In the trial context, facilitators will be two psychologists and a research nurse.

One-to-one sessions
Facilitators will deliver 7x one-to-one sessions to each participant. Further information on the structure of the intervention is available in Figure 2. Each session will include a combination of personalised and generic content. The intervention content and techniques were systematically developed and selected using Intervention Mapping 12 . Core strategies delivered to all participants will include those to increase self-efficacy, self-regulatory skills, and the automaticity of photoprotection. In addition, personalised modules will be delivered, as needed, selected initially based on data collected in Phase One studies and a profiling questionnaire, and iteratively as additional barriers emerge during the sessions. The facilitators will use a communication style consistent with Motivational Interviewing 26 .
They will be guided by a manual, including theory-based behaviour change techniques (BCTs) mapped to a recognised taxonomy 27 and specific techniques from other therapeutic approaches (e.g., Acceptance and Commitment Therapy) 28 .

Intervention materials
Patient-facing materials have been developed and will be provided to participants in session 1 and used throughout the intervention to facilitate discussion, provide real-life examples, and reinforce the concepts and skills discussed during the sessions. These are summarised in Figure 2.
[Please insert Figure 2 here]

Sample size calculations
The target sample size for the study is a total of 24 patients (i.e. 12 per group), which was based on the ability to detect an average daily UVR D-to-F difference of 0.10 SED between the groups during the June to July 2018 assessment period. This difference was considered clinically meaningful and potentially achievable due to the personalised nature of the intervention. From our Phase One study of UVR exposure, the average daily UVR Dto-F for people diagnosed with XP was 0.27 SED (SD=0.14), with a within-person correlation of r ICC =0.31. Thus the anticipated difference relates to an effect size of d=0.73, or just over a one-third reduction in average daily UVR D-to-F. Adjusting for the design effect due to the dependence of assessments within individuals, a sample size of 20 patients with 21 daily observations has 80% power to detect a reduction of 0.10 SED in average daily UVR D-to-F at the 5% significance level. Accounting for attrition of 20%, based on our previous research, the target sample size was set at 24.

Statistical analyses
The main efficacy analyses will be conducted by the trial statistician (SN) following a prespecified analysis plan and blind to group allocation. The analysis will follow the intention to treat principle with individuals analysed within the groups to which they were randomised irrespective of whether they received or persisted with the intervention.
The treatment effect on the primary outcome of daily UVR D-to-F over 21 days between June and July 2018 and secondary outcome of daily UVR D-to-F over 21 days in August will be estimated simultaneously using a linear mixed model. Given the skewed distribution of UVR D-to-F, a logarithmic transformation will be applied and robust standard errors will be estimated. A random intercept will account for the repeated assessments of UVR D-to-F within individuals across all 42 days, with an autoregressive error structure to account for correlation between assessments across successive days. In addition to the dummy coded group variable, other covariates in the model include a dummy coded variable for the assessment period (June-July vs August), an assessment period by group interaction, the patients baseline average daily UVR, an indictor variable for the patients propensity to burn, and the background level of UVR recorded by the observatory closest to the patients' house on the day. Data will be summarised as the empirical Bayes estimate of the average daily UVR D-to-F in SEDs for each assessment period for each group.
This approach allows for missing daily data within each individual under the assumption that data are missing at random We will run sensitivity analyses to explore the influence of missing data on the effect estimates, so as to allow for a consideration of the likely plausible range for the treatment effect under a number of missing not at random assumptions. For average daily assessments, where these are not available for the full 21 days, this will involve imputing missing values under a range of conservative assumptions using the average daily values of the group to which the individual is assigned using a pattern mixture model approach (e.g., average daily level + 0.0SED to 0.5SED).
Treatment effects for average daily levels of mood, self-efficacy, goal priority, automaticity and time outside will be analysed for both assessment periods simultaneously using mixed-effects as described above. Treatment effects for adherence, self-efficacy, automaticity, HRQoL, and psychological well-being taken at the start of the June and August assessment periods will also be estimated using linear mixed models but will specify an unconstrained error structure. It is not anticipated that transformation will be required to account for skew in any of these outcomes; however, robust standard errors will be estimated. Covariates included in the analysis will be the same as above except that baseline levels of the outcomes will be included in place of baseline average daily UVR D-to-F. Scale scores will be calculated using proration to account for missing items within the scale where there is at most one-third of items missing. For example, where scale includes 6 items, at least 4 items must have been completed otherwise the scale score will be set to missing for that individual.
Further exploratory analysis using dynamic regression models will evaluate changes in both level and variability in daily UVR exposure over time between March and September, accounting for treatment using a regression discontinuity approach. This is possible as the dosimeter will be worn for the entire period. However, due to patient burden and since the UVR protection diary is only completed for three-week intervals, it will also be necessary to calculate UVR D-to-F using average daily photoprotection during the pre and post diary intervals. This differs from the main analysis where UVR D-to-F is calculated directly based on photoprotection activities recorded on the diary.

Process evaluation
A mixed-methods process evaluation, using qualitative interviews and self-report measures, will explore the acceptability of the intervention, changes in photoprotection activities, and psychosocial mechanisms of change. A brief intervention feedback questionnaire, completed immediately after session 6, will be used to record more proximal perceptions of the main content of intervention. Responses to this questionnaire and the profiling questionnaire (see Figure 2) will be used to guide prompts during these interviews and give insight into psychosocial mechanisms of change.
The feedback questionnaire is adapted from one used to assess a fat reduction intervention 29 . It has 5-items assessing overall perceptions of the programme and its components, the impact on photoprotection activities, and whether psychosocial variables have changed as a result of the intervention. The questions assess the extent to which respondents agree with statements about the intervention (e.g., "Overall the programme was interesting" 1=strongly disagree -5=completely agree).
In-depth qualitative interviews will be conducted by a research nurse and health psychologist who were involved in the design and delivery of the intervention. They will not interview participants to whom they delivered the intervention. Interviews will be based on a topic guide and will explore participants' views of and experiences with XPAND, including more practical delivery-related aspects, such as the optimal number of sessions, preference for telephone or skype sessions, and the value of any further booster sessions. All interviews will be audio-recorded, transcribed, and coded using thematic analysis 30 31 in NVivo10.

Fidelity Assurance
A fidelity assessment will be undertaken to examine the extent to which facilitators delivered the key components of the intervention, specified in the intervention manual, during the face-to-face sessions. Independent researchers will apply a fidelity checklist to audio recordings of all session 1s and session 6s, as well as and a random selection of subsequent sessions.

Evaluation of the cost-utility of XPAND
A decision model will be used to assess the cost-effectiveness of the intervention.
Decision models allow outcomes and costs associated with alternative care process to be investigated via simulations. Model structures simplify the care process such that specific aspects can be focussed on. Advantages of these models are that they can be adapted to reflect the outcomes and costs that occur in a variety of settings (and therefore aid generalisability); they allow evidence to be generated in a time and cost-efficient way; and they enable interventions to be evaluated that may be precluded using trial methods. The structure of the model to be used here will be developed by the health economists in collaboration with the clinical researchers, and will consist of health states that patients may be in over time. Transition between the states will be informed by literature on the progression of the condition, expert opinion, and data collected through the trial. The impact of the intervention on these transitions will be determined through the clinical trial.
A health service perspective will be used followed by a societal perspective, which will incorporate broader costs.  32 . This retrospectively assesses use of primary and secondary healthcare services (including surgical interventions), social care, tests/investigations, and aids and adaptations (see supplementary files for Service Use Questionnaire). The cost of these inputs will be calculated by combining the service use data with appropriate unit cost information. Other impacts of XP include additional financial costs for the patient (e.g., sunscreen); and time lost from work/education by patients (e.g., to attend appointments, receive treatment, manage symptoms). Costs of these effects will be calculated using average wage rates and information on returns to education. Costs will be combined with quality-adjusted life years (QALYs) derived from the EQ-5D-5L. The estimated cost of the intervention will be based on staff time required to deliver it, plus additional training and materials.

Trial management
An independent Trial Steering Committee (TSC) attended by the research team, two independent researchers, and one PPI panel member will meet every 3 months to provide oversight of the trial. Trial data is collected after each measurement period by a member of the research team not delivering the intervention to that individual. Data are managed and entered by the research team, not the statisticians analysing the data. Adverse events are defined as events that occur during participation in the trial. All will be recorded [death; life threatening; hospitalisation; self-harm; attendance at A&E; distress (intervention group)] and reported to the TSC, who will make a judgement on the link to the trial and recommend modifications or discontinuing trial as appropriate. Patient and Public Involvement (PPI) has been integral to every step in the development of this protocol. The PPI panel advised on the study design, particularly related to participant burden of completion of the daily UVR protection diary, which informed the decision to limit the follow-up of the delayed intervention control group to a single period of 21 days (June-July 2019, t5). In addition, the panel reviewed all the XPAND intervention participant-facing materials which helped ensure they were appropriate and acceptable.

Patient and Public Involvement
The PPI panel were not involved in the recruitment process. A summary of research findings will be sent to all participants and published papers will be made available.

DISCUSSION
To the best of our knowledge this is the first RCT to test a behaviour change intervention to improve adherence to photoprotection in adults with XP; an ambitious undertaking in a rare disease. It uses a robust methodology, both in the systematic development of the intervention and in the use of a clinically-relevant novel measurement approach to estimate dose of UVR reaching the face. The inclusion of a process evaluation will provide insight into the workings of the intervention and the mechanism underlying our trial outcomes, as well as information about the acceptability of XPAND, a key consideration for the implementation of the intervention into routine clinical care. We will also have estimates of the cost-effectiveness of the intervention. Furthermore, over and above the obvious clinical advantages of decreasing the risk of morbidity and mortality associated with skin cancer for the XP population, if the trial is found to be efficacious, it will be of interest to those working in other long-term conditions which require photoprotection and may have significance for prevention of UVR-related skin damage in the healthy population.

This research has been approved by London -West London & GTAC Research Ethics
Committee 17/LO/2110. The findings will be published in peer reviewed journals and presented at national and international scientific conferences.

Trial status
Recruitment completed. Patient involvement in the study will conclude in December 2019.

Competing interests
None declared commenting on the final draft.         This booklet has your daily diary sheets to record when you were outside and whether you did anything to protect against UVR each day.

Contributors
� You only need to record the time you spend outside if it was for 10 minutes or longer � "OUTSIDE" is any amount of time longer than 10 minutes you did not spend in a building "OUTSIDE" includes time spent travelling in cars, buses or trains � Our grid is split into 15 minute blocks, start your line at the nearest block � If you can't remember exactly or you are unsure give us your best guess! � Try to fill out the diary at the end of each day. It will be easier to do when it is fresh in your mind. If you do forget, don't worry! Fill it out as soon as you remember. Thank you very much for taking the time to complete the daily diary.
Daily diary example overleaf Your daily diary UVR We are interested in your views about your UVR protection each day and your general mood. There are four short questions to complete. Don't take too long thinking about your responses. Your immediate reaction to each question will probably be more accurate than a long thought out response. Please circle the number that best corresponds to your views on that day.  Let us know if you wore any of these things today by marking a line on the diary  We know people adjust ultraviolet radiation (UVR) protection to fit in with their everyday life. We are interested in how you protected against UVR in the last week.

Please circle the number that best corresponds to your views:
Thinking about your UVR protection over the last week

We are interested in your own personal views about XP and ultraviolet (UVR)
protection. There are no right or wrong answers.
Answering these questions will help us tailor the XP and programme to your needs.
When we say UVR protection we mean anything you do to protect your face from UVR (e.g. sunscreen, clothing, staying indoors).
It will take about 5 minutes to complete.
Please circle the number that best corresponds to your views:

No Yes
Help in the house (for example cooking or cleaning)

No Yes
Help outside the house (for example shopping or transport)

No Yes
Going with you to medical appointment No Yes

If you answered yes to any help in the previous question, have your helper(s) taken any time out of work or education to help you as a result of your XP?
If there are part-days to consider, assume that 1 day = 8 hours. _____________ days taken off from work in the last 6 months _____________ days taken off from education in the last 6 months    How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial

Strengths and limitations of this study
 To the best of our knowledge, this is the first RCT to evaluate an adherence intervention designed to improve photoprotection in people diagnosed with XP.
 We have a primary outcome which is clinically relevant.
 We control for seasonal differences in environmental UVR exposure by comparing between groups across the same weeks.
 We include a process evaluation to understand participant views of XPAND which will be important when integrating the intervention into current clinical care.

INTRODUCTION
Xeroderma Pigmentosum (XP) is a very rare genetic condition, where the body is unable to repair ultraviolet radiation (UVR)-induced damage to DNA caused by daylight 1 .
Any UVR exposure dramatically increases the chances of developing skin and eye cancers (e.g., rates of non-melanoma skin cancer increase 10,000 fold) 2 . Photoprotection is recommended for the healthy population and those taking medications which may cause photosensitivity. However, it is essential for people with XP. There is currently no cure for this disease and the only way to minimise and delay the cancers is meticulous and absolute photoprotection every day. Photoprotection involves a complex set of behaviours (i.e., application of broad-spectrum SPF50 sunscreen, wearing long sleeves and long trousers or skirts, wide brimmed hat, glasses, face scarf or buff and avoiding UVR exposure by staying indoors). The best way of protecting the face is by wearing a face visor (a legionnaire style hat with a UVR-protective transparent film at the front). Analysis of self-reported photoprotection used by 21 adults with XP in the UK revealed that over half were using 'very poor' or no photoprotection for at least 20% of all outdoor time 3 . This poor photoprotection has life-threatening consequences.
We aimed to systematically develop an adherence intervention to improve photoprotection in XP. There is growing support for interventions focused on changing patient beliefs about their illness and treatment, translating into improvements in adherence across a range of chronic conditions [8][9][10] . This suggests that addressing unhelpful illness and treatment beliefs may be an important treatment target for photoprotection in XP. Furthermore, a recent systematic review found evidence in support of the effectiveness of psychosocial interventions to improve adherence to photoprotective activities among non-XP individuals at elevated risk for melanoma (due to personal or family history 11 ).
We designed a personalised intervention titled, 'XPAND: Enhancing XP Photoprotection Activities -New Directions', using Intervention Mapping 12 . Intervention Mapping starts by breaking the desired behaviour and determinants of behaviour into constituent parts, which are mapped to theory and translated to intervention components.
This paper describes the protocol for a randomised controlled trial (RCT) to test the efficacy of XPAND to lower the dose of UVR reaching the face, by improving adherence to photoprotection. This can be achieved by minimising overall UVR exposure (i.e., time spent outside) and by increasing level of photoprotection worn or applied when outside. The primary objective is to reduce the average daily UVR dose to the face (D-to-F) across 21 days in June to July (2018), immediately after the delivery of the main intervention. Secondary objectives are: to maintain reductions in average daily UVR D-to-F across 21 days in August 2018 (after a booster session has been delivered to the intervention group); to increase and then maintain daily ratings of mood, self-efficacy, goal priority, automaticity and photoprotection activities across the two 21-day periods. Tertiary objectives are to explore intervention-related changes from baseline. A qualitative process evaluation will investigate the acceptability, feasibility, and change mechanisms from the perspective of the participant. We will conduct a cost-utility analysis, which will indicate whether implementation into clinical care is economically viable.

Study design and flowchart
The XPAND trial is a phase-II two-armed parallel group RCT, with a delayed intervention control arm. Participants are randomised to either the intervention group who receive the XPAND intervention in addition to routine care between April and June 2018 or to the control group who receive routine care in 2018 and then XPAND between April and June 2019. The delayed intervention control group is included to maximise information collection about the intervention due to the extremely rare nature of XP. For example, achievable sample sizes limit the ability to test between-group differences for the psychosocial outcomes with acceptable power and the delayed intervention group allows for intervention-related changes from baseline testing, which is less robust but still useful.
[please insert Figure 1 here] The study is funded by the NIHR Programme Grants for Applied Research scheme (RP-

Randomisation
Participants will be randomised, in blocks using an equal allocation ratio, to receive XPAND immediately (2018) or to the delayed group stratified by burning type to attempt to balance those with an extreme (i.e., scoring between 1-3 on the sunburn severity score 18 ) versus normal burning response. Participants who are in the same family will be randomised as a cluster to the same group to avoid contamination. Since all participants will be recruited at the point of randomisation, the trial statistician (SN) will generate a random allocation sequence for all participants together, using a computer programme with fixed block sizes of 4, to ensure equal allocation to both groups. To protect the integrity of the randomisation, participants in the immediate intervention group will be asked not to reveal their allocation to those outside their immediate family. Group allocation will be concealed from the XP clinical team who are not part of the research team (excluding the PI) to avoid inadvertent changes to the standard care of these participants during the trial (e.g.,  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  greater/lesser discussion of adherence during routine clinical appointments). Moreover, as both the control and intervention groups might receive opportunistic encouragement from the clinical team to protect, this would not adversely affect the trial outcome.

Primary outcome
The primary outcome is the average daily UVR D-to-F (standard erythemal dose; SED), across 21 consecutive days between June and July 2018 (t1), following completion of six out of seven intervention sessions by the intervention group. UVR D-to-F is estimated by combining data from a UVR dosimeter worn on the wrist (SunSaver 3, Bispebjerg Hospital, Copenhagen, Denmark) 19 and the patient's photoprotective activities, self-reported using the daily UVR protection diary. The dosimeter was set to measure UVR levels every five seconds and record the average every 5 minutes, which has been validated as providing reliable measurements of total UVR exposure over the course of a day 20

Secondary outcomes
The following outcomes relate to between-group comparisons in 2018 and are recorded on the daily UVR protection diary. UVR-related outcomes also use data from the dosimeter.
a. Average daily UVR D-to-F across 21 consecutive days in August 2018 (t2). This is to investigate the stability of any improvement identified in the primary outcome period (June-to-July 2018), as it will be 4-6 weeks after the main intervention and follows session 7 (the booster session).
b. Average daily total UVR exposure during each of the 21-day periods (t1, t2) and the average daily time outside across all daylight hours and restricted to 11-3pm, when UVR levels are at their highest. This data will be gathered from the dosimeter and the UVR protection diary.  prioritisation of photoprotection compared to other priorities, and level of selfefficacy to manage barriers during the two follow-up periods (t1, t2) will be assessed. The single items have been adapted from ecological momentary assessment questions used in our n-of-1 study 3 (e.g., How much do you agree that UVR protection of your face today was something you did automatically without thinking 0=strongly disagree -10=strongly agree) and are included on the UVR protection diary (see Supplementary file 1.).

Tertiary outcomes
The following outcomes are assessed once, at the start of each 21-day period (t0, t1, t2, t3). Health-related quality of life (HRQoL), psychological well-being, automaticity of photoprotection activities, self-efficacy in the context of barriers, and self-rated photoprotection adherence will be measured using self-report questionnaires. Data will be combined across t1 and t2 to assess proximal impact of the intervention and t3 will be used to assess stability of impact.
See Table 1 for the schedule of self-reported measures.
a. HRQoL will be assessed using the EQ-5D-5L 21 b. Emotional well-being will be measured by the Short-form Warwick Edinburgh Mental Well-Being scale (SWEMWBS) 22 c. Automaticity of photoprotection activities will be assessed using the 4-item Self-Report Behavioural Automaticity Index (SRBAI) 23 , adapted to photoprotection. It is a validated during the previous 7 days. Three items assess different ways of protecting outdoors: how often respondents wore protective clothing (e.g., When you went outside, how often did you protect your face against UVR using protective clothing? 0=never -10=all the time); the number of days sunscreen was applied in the morning (0-7 days); and how often sunscreen was re-applied when outdoors for longer periods (0=not at all -10=always). Two items ask respondents to estimate average duration of time outdoors each day (Never, <30mins, 31mins-1 hour, 2 hours, upwards in hourly intervals to >8 hours) and average duration of time outdoors each day between 11am-3pm when environmental UVR levels are highest. Each item will be analysed separately.
Further exploratory analyses will examine change from baseline incorporating the delayed intervention group allowing for higher power to assess intervention-related changes. These will be undertaken unblinded to group allocation after main efficacy analyses are complete.

The XPAND intervention
XPAND is composed of a combination of one-to-one sessions and materials purposedesigned to target barriers to photoprotection. It was designed to be delivered by a healthcare professional (HCP) without specialist psychological training (e.g., clinical nurse specialist). In the trial context, facilitators will be two psychologists and a research nurse.

One-to-one sessions
Facilitators will deliver 7x one-to-one sessions to each participant. Further information on the structure of the intervention is available in Figure 2. Each session will include a combination of personalised and generic content. The intervention content and techniques were systematically developed and selected using Intervention Mapping 12 . Core strategies delivered to all participants will include those to increase self-efficacy, self-regulatory skills, and the automaticity of photoprotection. In addition, personalised modules will be delivered, as needed, selected initially based on data collected in Phase One studies and a profiling questionnaire, and iteratively as additional barriers emerge during the sessions.
The facilitators will use a communication style consistent with Motivational Interviewing 26 .
They will be guided by a manual, including theory-based behaviour change techniques (BCTs) mapped to a recognised taxonomy 27 and specific techniques from other therapeutic approaches (e.g., Acceptance and Commitment Therapy) 28 .

Intervention materials
Patient-facing materials have been developed and will be provided to participants in session 1 and used throughout the intervention to facilitate discussion, provide real-life examples, and reinforce the concepts and skills discussed during the sessions. These are summarised in Figure 2.
[Please insert Figure 2 here]

Sample size calculations
The target sample size for the study is a total of 24 patients (i.e. 12 per group), which was based on the ability to detect an average daily UVR D-to-F difference of 0.10 SED between the groups during the June to July 2018 assessment period. This difference was considered clinically meaningful and potentially achievable due to the personalised nature of the intervention. From our Phase One study of UVR exposure, the average daily UVR Dto-F for people diagnosed with XP was 0.27 SED (SD=0.14), with a within-person correlation of r ICC =0.31. Thus the anticipated difference relates to an effect size of d=0.73, or just over a one-third reduction in average daily UVR D-to-F. Adjusting for the design effect due to the dependence of assessments within individuals, a sample size of 20 patients with 21 daily observations has 80% power to detect a reduction of 0.10 SED in average daily UVR D-to-F at the 5% significance level. Accounting for attrition of 20%, based on our previous research, the target sample size was set at 24. The main efficacy analyses will be conducted by the trial statistician (SN) following a prespecified analysis plan and blind to group allocation. The analysis will follow the intention to treat principle with individuals analysed within the groups to which they were randomised irrespective of whether they received or persisted with the intervention.

Statistical analyses
The treatment effect on the primary outcome of daily UVR D-to-F over 21 days between June and July 2018 and secondary outcome of daily UVR D-to-F over 21 days in August will be estimated simultaneously using a linear mixed model. Given the skewed distribution of UVR D-to-F, a logarithmic transformation will be applied and robust standard errors will be estimated. A random intercept will account for the repeated assessments of UVR D-to-F within individuals across all 42 days, with an autoregressive error structure to account for correlation between assessments across successive days. In addition to the dummy coded group variable, other covariates in the model include a dummy coded variable for the assessment period (June-July vs August), an assessment period by group interaction, the patients baseline average daily UVR, an indictor variable for the patients propensity to burn, and the background level of UVR recorded by the observatory closest to the patients' house on the day. Data will be summarised as the empirical Bayes estimate of the average daily UVR D-to-F in SEDs for each assessment period for each group.
This approach allows for missing daily data within each individual under the assumption that data are missing at random. We will run sensitivity analyses to explore the influence of missing data on the effect estimates, so as to allow for a consideration of the likely plausible range for the treatment effect under a number of missing not at random assumptions. For average daily assessments, where these are not available for the full 21 days, this will involve imputing missing values under a range of conservative assumptions using the average daily values of the group to which the individual is assigned using a pattern mixture model approach (e.g., average daily level + 0.0SED to 0.5SED).
Treatment effects for average daily levels of mood, self-efficacy, goal priority, automaticity and time outside will be analysed for both assessment periods simultaneously using mixed-effects as described above. Treatment effects for adherence, self-efficacy, automaticity, HRQoL, and psychological well-being taken at the start of the June and August assessment periods will also be estimated using linear mixed models but will specify an unconstrained error structure. It is not anticipated that transformation will be required to account for skew in any of these outcomes; however, robust standard errors will be estimated. Covariates included in the analysis will be the same as above except that baseline levels of the outcomes will be included in place of baseline average daily UVR D-to-F. Scale scores will be calculated using proration to account for missing items within the scale where there is at most one-third of items missing. For example, where scale includes 6 items, at least 4 items must have been completed otherwise the scale score will be set to missing for that individual.
Further exploratory analysis using dynamic regression models will evaluate changes in both level and variability in daily UVR exposure over time between March and September, accounting for treatment using a regression discontinuity approach. This is possible as the dosimeter will be worn for the entire period. However, due to patient burden and since the UVR protection diary is only completed for three-week intervals, it will also be necessary to calculate UVR D-to-F using average daily photoprotection during the pre and post diary intervals. This differs from the main analysis where UVR D-to-F is calculated directly based on photoprotection activities recorded on the diary.

Process evaluation
A mixed-methods process evaluation, using qualitative interviews and self-report measures, will explore the acceptability of the intervention, changes in photoprotection activities, and psychosocial mechanisms of change. A brief intervention feedback questionnaire, completed immediately after session 6, will be used to record more proximal perceptions of the main content of intervention. Responses to this questionnaire and the profiling questionnaire (see Figure 2) will be used to guide prompts during these interviews and give insight into psychosocial mechanisms of change.
The feedback questionnaire is adapted from one used to assess a fat reduction intervention 29 . It has 5-items assessing overall perceptions of the programme and its components, the impact on photoprotection activities, and whether psychosocial variables have changed as a result of the intervention. The questions assess the extent to which respondents agree with statements about the intervention (e.g., "Overall the programme was interesting" 1=strongly disagree -5=completely agree) (see Supplementary file 4.).
In-depth qualitative interviews will be conducted by a research nurse and health psychologist who were involved in the design and delivery of the intervention. They will not interview participants to whom they delivered the intervention. Interviews will be based on a topic guide and will explore participants' views of and experiences with XPAND, including more practical delivery-related aspects, such as the optimal number of sessions, preference for telephone or skype sessions, and the value of any further booster sessions. All interviews will be audio-recorded, transcribed, and coded using thematic analysis 30 31 in NVivo10. A fidelity assessment will be undertaken to examine the extent to which facilitators delivered the key components of the intervention, specified in the intervention manual, during the face-to-face sessions. Independent researchers will apply a fidelity checklist to audio recordings of all session 1s and session 6s, as well as and a random selection of subsequent sessions.

Evaluation of the cost-utility of XPAND
A decision model will be used to assess the cost-effectiveness of the intervention.
Decision models allow outcomes and costs associated with alternative care process to be investigated via simulations. Model structures simplify the care process such that specific aspects can be focussed on. Advantages of these models are that they can be adapted to reflect the outcomes and costs that occur in a variety of settings (and therefore aid generalisability); they allow evidence to be generated in a time and cost-efficient way; and they enable interventions to be evaluated that may be precluded using trial methods. The structure of the model to be used here will be developed by the health economists in collaboration with the clinical researchers, and will consist of health states that patients may be in over time. Transition between the states will be informed by literature on the progression of the condition, expert opinion, and data collected through the trial. The impact of the intervention on these transitions will be determined through the clinical trial.
A health service perspective will be used followed by a societal perspective, which will incorporate broader costs.
Service use will be measured via completion of a Client Service Receipt Inventory (CSRI) 32 . This retrospectively assesses use of primary and secondary healthcare services (including surgical interventions), social care, tests/investigations, and aids and adaptations (see Supplementary file 5.). The cost of these inputs will be calculated by combining the service use data with appropriate unit cost information. Other impacts of XP include additional financial costs for the patient (e.g., sunscreen); and time lost from work/education by patients (e.g., to attend appointments, receive treatment, manage symptoms). Costs of these effects will be calculated using average wage rates and information on returns to education. Costs will be combined with quality-adjusted life years (QALYs) derived from the EQ-5D-5L. The estimated cost of the intervention will be based on staff time required to deliver it, plus additional training and materials.

Trial management
An independent Trial Steering Committee (TSC) attended by the research team, two independent researchers, and one PPI panel member will meet every 3 months to provide oversight of the trial. Trial data is collected after each measurement period by a member of the research team not delivering the intervention to that individual. Data are managed and entered by the research team, not the statisticians analysing the data. Adverse events are defined as events that occur during participation in the trial. All will be recorded [death; life threatening; hospitalisation; self-harm; attendance at A&E; distress (intervention group)] and reported to the TSC, who will make a judgement on the link to the trial and recommend modifications or discontinuing trial as appropriate.

Patient and Public Involvement
Patient and Public Involvement (PPI) has been integral to every step in the development of this protocol. The PPI panel advised on the study design, particularly related to participant burden of completion of the daily UVR protection diary, which informed the decision to limit the follow-up of the delayed intervention control group to a single period of  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  The PPI panel were not involved in the recruitment process. A summary of research findings will be sent to all participants and published papers will be made available.

No Yes
Help in the house (for example cooking or cleaning)

No Yes
Help outside the house (for example shopping or transport)

No Yes
Going with you to medical appointment No Yes 9. If you answered yes to any help in the previous question, have your helper(s) taken any time out of work or education to help you as a result of your XP? If there are part-days to consider, assume that 1 day = 8 hours. _____________ days taken off from work in the last 6 months _____________ days taken off from education in the last 6 months   Table 1 Page 51 of 55

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions 10 Allocation concealmen t mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 10 Implementat ion 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions 10 Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how 10, 16 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial Can be obtained from authors

Data collection methods 18a
Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol Definition of analysis population relating to protocol nonadherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation)

9-15
Can be obtained from authors

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed 20-21 21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial n/a

Harms 22
Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct